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Pathogenic Effects of Cerebral Amyloid Angiopathy Mutations in the Amyloid β‐Protein Precursor
Author(s) -
NOSTRAND WILLIAM E.,
MELCHOR JERRY P.,
ROMANOV GALINA,
ZEIGLER KELLY,
DAVIS JUDIANNE
Publication year - 2002
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2002.tb04824.x
Subject(s) - cerebral amyloid angiopathy , mutant , fibrillogenesis , genetically modified mouse , mutation , amyloid precursor protein , protein precursor , amyloid (mycology) , angiopathy , p3 peptide , microbiology and biotechnology , chemistry , biology , transgene , fibril , alzheimer's disease , gene , pathology , biochemistry , medicine , endocrinology , disease , dementia , diabetes mellitus , inorganic chemistry
A bstract : Cerebral amyloid β‐protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Aβ region of the Aβ protein precursor (AβPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Aβ region (D23N) of AβPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double‐mutant Aβ40 peptides rapidly assemble in solution to form fibrils compared to wild‐type Aβ40. Similarly, the E22Q Dutch and D23N Iowa Aβ40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell‐associated AβPP, proteolytic breakdown of actin, and cell death. Double‐mutant E22Q/D23N Dutch/Iowa Aβ40 was more potent than either single‐mutant form of Aβ in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Aβ towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Aβ peptide further enhances the fibrillogenic and pathogenic properties of Aβ. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AβPP in vivo . Preliminary analysis of transgenic mouse brains indicates that expression of double‐mutant E22Q/D23N Dutch/Iowa AβPP leads to robust deposition of Aβ in a vascular‐weighted manner.